The present invention relates to an oral dosage form comprising crystalline lopinavir and crystalline ritonavir, wherein the crystalline lopinavir is present in a mixture with a brittle vehicle. The invention further relates to methods of preparing said oral dosage forms containing the above pharmaceutical active agents.
“Lopinavir” is reported to be the INN name of (2S)—N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide and is characterized by the following chemical formula (I):

Lopinavir is reported to be an antiretroviral active substance, a member of the protease inhibitors (PI), which are used to treat or prevent infections caused by viruses. Proteases are enzymes used by viruses to cleave proteins for the final assembly of new virions. In the case of lopinavir, especially the prevention of viral replication by inhibiting the activity of proteases, such as HIV-1 protease, are reported.
“Ritonavir” is reported to be the INN name of 1,3-thiazol-5-ylmethylN-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl})carbamoyl]amino}butanamido]-1,6-diphenylhexan-2-yl]carbamate and is characterized by the following chemical formula (II):

Ritonavir is also reported to be a member of the class of protease inhibitors and is used in the treatment of HIV infection and AIDS. However, ritonavir is frequently described as being used in a combination with other antiretroviral drugs due to its capability to inhibit the same host enzyme that metabolizes other protease inhibitors. Due to this inhibition of the above host enzyme, the plasma concentrations of the further protease-inhibiting drugs tend to be higher so that their dose and frequency in administration can be lowered.
EP 1 663 183 B1 describes a solid pharmaceutical composition comprising ritonavir. The pharmaceutical composition can optionally comprise further protease inhibitors, such as lopinavir, indinavir and saquinavir. However, it turned out that the compositions described in the art show a dissolution and plasma profile which can be improved, especially during the first 30 minutes after administration. Also content uniformity of those compositions is still improvable.
Further, it turned out that the known compositions have to be processed within a very small and specific range of process parameters, i.e. the manufacturing process and thus the quality of the resulting products is device dependent.
Additionally, the storage stability of the prior art compositions is often not satisfactory, especially when stored under conditions of climate zones III and IV. These climate zones are characterized by a temperature of 30° C. and a relative humidity of 35% (climate zone III) and of 70% (climate zone IV).
Hence, it was an object of the present invention to overcome the drawbacks of the prior art compositions. Consequently, an oral dosage form comprising a combination of lopinavir and ritonavir and having superior in-vitro and in-vivo properties should be provided, preferably in combination with excellent content uniformity. Any food effect should be minimized. In particular, an oral dosage form should be provided with improved in-vitro properties, such as excellent dissolution within the first 45 minutes. Further, in the dissolution profile, any lag time should be prevented. The lag time should preferably be prevented even in case the oral dosage form is coated with a commercially obtainable HPMC-coating. The dosage form should comprise only minor amounts of decomposition products. Those advantages should be achievable even under the harsh storage conditions of climate zones III and IV. Further, the dosage form should be producible by a predominantly device-independent manufacturing process.